WO2021152476A1 - Système et procédé pour la génération d'un jet microfluidique à partir d'un dispositif compact - Google Patents

Système et procédé pour la génération d'un jet microfluidique à partir d'un dispositif compact Download PDF

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Publication number
WO2021152476A1
WO2021152476A1 PCT/IB2021/050625 IB2021050625W WO2021152476A1 WO 2021152476 A1 WO2021152476 A1 WO 2021152476A1 IB 2021050625 W IB2021050625 W IB 2021050625W WO 2021152476 A1 WO2021152476 A1 WO 2021152476A1
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WO
WIPO (PCT)
Prior art keywords
fluid
nozzle
substrate
jet
radiation
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PCT/IB2021/050625
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English (en)
Inventor
Jan Krizek
Christophe Moser
Frédéric DE GOUMOËNS
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Ecole Polytechnique Federale De Lausanne (Epfl)
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Priority to US17/783,690 priority Critical patent/US20230026586A1/en
Publication of WO2021152476A1 publication Critical patent/WO2021152476A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/20—Automatic syringes, e.g. with automatically actuated piston rod, with automatic needle injection, filling automatically
    • A61M5/2046—Media being expelled from injector by gas generation, e.g. explosive charge
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B18/22—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B18/22—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor
    • A61B18/26—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor for producing a shock wave, e.g. laser lithotripsy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/20—Automatic syringes, e.g. with automatically actuated piston rod, with automatic needle injection, filling automatically
    • A61M5/204—Automatic syringes, e.g. with automatically actuated piston rod, with automatic needle injection, filling automatically connected to external reservoirs for multiple refilling
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/30—Syringes for injection by jet action, without needle, e.g. for use with replaceable ampoules or carpules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B18/22—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor
    • A61B18/28—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor for heating a thermal probe or absorber
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B2018/2005—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser with beam delivery through an interstitially insertable device, e.g. needle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B18/22—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor
    • A61B2018/2205—Characteristics of fibres
    • A61B2018/2211—Plurality of fibres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B18/22—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor
    • A61B2018/2255—Optical elements at the distal end of probe tips
    • A61B2018/2266—Optical elements at the distal end of probe tips with a lens, e.g. ball tipped
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B18/22—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor
    • A61B18/26—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor for producing a shock wave, e.g. laser lithotripsy
    • A61B2018/263—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor for producing a shock wave, e.g. laser lithotripsy the conversion of laser energy into mechanical shockwaves taking place in a liquid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B18/22—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor
    • A61B18/26—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor for producing a shock wave, e.g. laser lithotripsy
    • A61B2018/266—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor for producing a shock wave, e.g. laser lithotripsy the conversion of laser energy into mechanical shockwaves taking place in a part of the probe
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/36—General characteristics of the apparatus related to heating or cooling

Definitions

  • the present invention relates to a system and a method for generation of microfluidic jets. More particularly, the present invention provides a device and a method for controlled delivery of small amounts of liquids, e.g., medicaments, using microjets generated from a compact system.
  • liquids e.g., medicaments
  • Needle injection is one of the classical routes for localized drug delivery. But the current challenge is not only in the system miniaturization but also in the precision of the drug dose delivery and its spatial localization. Jet injection technique is a promising candidate to solve dosing and localization problem, however, in the present art, there is a lack of solutions providing compact systems allowing operation in physically restricted areas or schemes capable of parallelization of the delivery process from multiple units such as is proposed in US 2004/0260234 Al.
  • a convenient method for a pressure and consequent jet generation is by using lasers.
  • Laser radiation causes fast vaporization of the fluid and consequent bubble expansion generates driving pressure force for the jet.
  • Documents US 8905966 B2, US 2015/0265770 Al, US 2012/0215098 Al, US 9351817 B1 describe systems which consist of two separate compartments: one for the light absorption driving fluid and the second is the channel for the drug content, the pressure is then transmitted by an elastic membrane. As the mechanical energy is mediated through the membrane it requires a significant laser energy pulse (>100 mJ) to produce liquid jets of sufficient power.
  • Another laser jet generating apparatus has been proposed as a dissection device US 7815632 B2, US 7740626 B2.
  • the actuation scheme is realized by a high energy nano second light pulse delivered by an optical fiber directly to the ejected fluid.
  • the proposed solution relies on a high energy laser source generating nano second pulses of significant energy (>50 mJ) which exclude the use of thin optical fibers ( ⁇ 500 pm) due to potentially high energy densities and limiting laser induced damage threshold.
  • Using lower energy actuation ( ⁇ 10 mJ) in the aforementioned schemes would generate jet of insufficient power to penetrate into a broad range of body tissue.
  • High energy generation requirement necessitate costly and large laser systems. Therefore, there is a need to augment the effectiveness of energy translation between a laser radiation and a liquid jet.
  • optical fibers or other waveguides unfolds the potential of lasers as a driving mechanism.
  • the fact that the energy can be remotely generated in a large laser system and then delivered by means of very thin and flexible fibers is convenient for miniaturization of the jet delivery device. Flexibility adds opportunity to make devices compatible with minimally invasive surgical techniques, such as for example endoscopy or others.
  • a specific dynamics of the generation allows taking advantage of the flow focusing phenomena such as described by Tagawa et.al. (https://doi.org/10.1103/PhysRevN.2.031002).
  • the compactness of the optical fiber allows to design new schemes for needle-assisted fluid delivery. Accordingly, the present invention aims to provide a solution to miniaturization of the jet injection technology.
  • the invention provides a method for jet ejection of a fluid towards a substrate, comprising providing a nozzle filled inside with the fluid, positioning a fiber source of pulsed radiation inside the nozzle in direct contact with the fluid, the fiber source comprising an optical fiber.
  • the fluid is configured to absorb at least a part of the radiation.
  • the method further comprises generating a bubble inside the nozzle by absorbing a pulse of the pulsed radiation in a first portion of the fluid, thereby vaporizing the fluid into the bubble, pushing a second portion of the fluid out of an opening at an extremity of the nozzle by an effect of an expansion of the bubble, whereby the extremity is directed to the substrate, thereby enabling the jet ejection of the second portion of fluid, and an intensity of the pulse being configured to be inferior to a radiation-induced threshold of a material comprised in the fiber source.
  • the method further comprises adding an absorbing additive to the fluid, the absorbing additive being configured to improve the absorption of the pulse in the fluid and the vaporization thereof.
  • the source of laser pulses emits in the spectrum which is intrinsically absorbed by the liquid.
  • interaction of the short pulse ( ⁇ 100 ns) laser radiation with the liquid can happen under heat and stress confined conditions which mitigates degrading effects on the sensitive formulations.
  • the method further comprises integrating a focusing mechanism in the fiber source configured to focus radiation out of the optical fiber, thereby enabling an increase of the intensity of the pulse.
  • the method further comprises positioning the extremity in a gaseous environment, and providing a layer of hydrophilic material at the opening, thereby enabling a formation of a concave meniscus directed to the inside of the nozzle, the concave meniscus defining an interface between the fluid and the gaseous environment, the concave meniscus being configured to center the jet ejection in the nozzle, and accelerate the jet ejection by a flow focusing effect.
  • the method further comprises positioning the extremity in a liquid environment, introducing at the extremity a determined volume of gas to enable a controlled gas bubble creation between the substrate and an end of the fiber source, thereby enabling a formation of a concave meniscus directed to the inside of the tubular nozzle, the concave meniscus defining an interface between the fluid and the controlled gas bubble environment, the concave meniscus being configured to center the jet ejection in the nozzle, and accelerate the jet ejection by a flow focusing effect.
  • the method further comprises configuring the intensity, an absorption of the pulse in the fluid, and the formation of the concave meniscus such to enable the second portion to penetrate into the substrate.
  • the step of configuring is such to enable the second portion to pierce the substrate.
  • the method further comprises configuring the intensity, an absorption of the pulse in the fluid, and the formation of the concave meniscus such to enable the second portion to be deposited on a top of the substrate.
  • the substrate is a biological tissue.
  • the method further comprises providing further nozzles filled inside with the fluid, and positioning further fiber sources of pulsed radiation respectively inside the corresponding nozzle in direct contact with the fluid, thereby enabling to concurrently generate the jet ejection for each nozzle.
  • the invention provides a method for a needle assisted jet injection of a fluid in a substrate, comprising piercing the substrate with an injection needle, and applying pressure by means of a pressure generating mechanism, to the fluid at an entrance side of the injection needle to inject the fluid through the injection needle.
  • the step of applying a pressure involves causing a rapid phase transition of a first portion of the fluid, thereby generating a bubble configured to expand and inject a second portion of fluid through the injection needle.
  • the pressure generating mechanism comprises a pulsed radiation source.
  • the pressure generating mechanism comprises an electrical discharge source.
  • the pressure generating mechanism comprises a compartment configured to be filled by the fluid, and fluidically connected to the entrance side of the injection needle.
  • the compartment further comprises a window transparent to the pulsed radiation source.
  • the compartment further comprises a separation part configured to absorb the pulsed radiation and thereby lead to the rapid phase transition of the first portion of the fluid.
  • the step of applying pressure is further configured to enable an adjustment of a depth in the substrate at which the fluid may be jet injected.
  • the method further comprises generating a bubble inside the nozzle by absorbing a pulse of the pulsed radiation in a first portion the fluid, thereby vaporizing the fluid into the bubble, pushing a second portion of the fluid out of an opening at an extremity of the nozzle by an effect of an expansion of the bubble, whereby the extremity is directed to the substrate, thereby enabling the jet injection of the second portion of fluid, and an intensity of the pulse being configured to be inferior to a radiation-induced threshold of a material comprised in the fiber source.
  • the invention provides a method for a needle assisted jet injection of a first fluid in a substrate, comprising piercing the substrate with an injection needle, applying pressure by means of a pressure generating mechanism, to the first fluid at an entrance side of the injection needle to inject the first fluid through the injection needle, and providing a first compartment configured to contain the first fluid.
  • the step of applying pressure further comprises providing a second compartment configured to contain a second fluid, and causing a rapid phase transition of a portion of the second fluid, thereby generating a bubble configured to expand, apply pressure to the first compartment, and inject a part of the first fluid though the injection needle.
  • the pressure generating mechanism comprises a pulsed radiation source. In a further preferred embodiment, the pressure generating mechanism comprises an electrical discharge source.
  • the invention provides a jet ejection device for jet ejection of a fluid towards an intended substrate, comprising a nozzle, a fiber source of pulsed radiation positioned inside the nozzle, the fiber source comprising an optical fiber, the nozzle being filled inside with the fluid, and the fiber source being in direct contact with the fluid.
  • the fluid is further configured to absorb at least a part of the radiation and to generate a bubble inside the nozzle when a pulse of the pulsed radiation is absorbed in a first portion of the fluid and vaporizes the fluid into the bubble, whereby an effect of expansion of the bubble causes a second portion of the fluid to be pushed to an opening at an extremity of the nozzle directed to the intended substrate, thereby enabling the jet ejection of the second portion of fluid.
  • the jet ejection device further comprises an absorbing additive for the fluid, configured to improve absorption of the pulse in the fluid and the vaporization thereof.
  • the jet ejection device further comprises a focusing mechanism in the fiber source configured to focus radiation out of the optical fiber, thereby enabling an increase of the intensity of the pulse.
  • the jet ejection device further comprises a layer of hydrophilic material at the opening, configured to enable a formation of a concave meniscus directed to the inside of the nozzle, the concave meniscus defining an interface between the fluid and a gaseous environment at the opening of the nozzle, the concave meniscus being configured to center the jet ejection in the nozzle and accelerate the jet ejection by a flow focusing effect.
  • the jet ejection device further comprises a gas channel configured to deliver gas at the opening of the nozzle, and thereby to enable the formation of the concave meniscus.
  • the jet ejection device further comprises a flexible tubing leading to the nozzle
  • the invention provides a needle assisted jet injection device for injection of a fluid in an intended substrate, the device comprising an injection needle, having an entrance side through which fluid enters the injection needle, a fluid supply channel configured to supply the fluid, whereby the entrance side of the injection needle is attached to an output of the fluid supply channel, a pressure generating mechanism configured to apply pressure to the fluid at the entrance side of the injection needle.
  • the pressure generating mechanism comprises a pulsed energy supply configured to deliver a pulse of energy in the fluid in the vicinity of the entrance side, thereby causing a rapid phase transition of a first portion of the fluid and generating a bubble configured to expand and inject a second portion of fluid through the injection needle.
  • the pulsed energy supply comprises a pulsed radiation source.
  • the pulsed energy supply comprises an electrical discharge source.
  • the invention provides a use of the jet ejection device as described herein above, to achieve any one of the following list: injection of the fluid in the substrate, depositing of the fluid on the substrate, injection of the fluid through the substrate.
  • the invention provides a use of the needle assisted jet injection device as described herein above, to achieve any one of the following list: injection of the fluid in the substrate, depositing of the fluid on the substrate, injection of the fluid through the substrate.
  • the invention provides a patterned arrangement of multiple nozzles such as described in the first aspect herein above.
  • the patterned arrangement comprises a radiation splitting means configured to generate a plurality of partition of radiation, each partition corresponding to a respective nozzle of the multiple nozzles.
  • the radiation splitting means is any one of the items in the list comprising at least a beam splitter, a lens microarray, a hologram, a fiber-based splitter, a fiber bundle system.
  • Figure 1 contains a schematic of a compact system generating liquid microjet (107) in the gaseous environment (102) by a laser actuation (105) with a source having direct contact with ejected fluid by optical fiber (106), whereby in FIGla the drawing depicts the status of the system before the liquid jet emerges, and in FIGlb the drawing depicts the status of the system after the liquid jet emerges;
  • Figure 2 contains a schematic example of arrangement of multiple embodiments from Figure 1 to concurrently generate multiple liquid microjets in the air environment
  • Figure 3 contains a schematic of a compact system to generate liquid microjet (308) in the liquid environment (301) with a gas channel (305) allowing bubble generation (306) at the channel opening, whereby in FIG3a the drawing depicts the status of the system before the liquid jet emerges, and in FIG3b: the drawing depicts the status of the system after the liquid jet emerges;
  • Figure 4 contains a schematic depiction of the needle assisted (401) jet injection using a vapor bubble (405) pressure generation scheme (402) in the direct contact to a released fluid;
  • Figure 5 contains a schematic example of arrangement of multiple systems from Figure 4 to concurrently generate multiple liquid injections from the needle-assisted jet injectors;
  • Figure 6 contains a schematic view of a needle assisted jet injection system using electromagnetic radiation (603) as a driving force for the liquid jet actuation while the source of the radiation is comparted from the fluid (606) by separation (601) transparent to the radiation; variations of the actuation scheme:
  • FIG6a a source of radiation is delivered by an optical waveguide (602) and is further absorbed by the fluid (606);
  • FIG6b radiation (609) is focused by e.g., lens (610) and passes through a transparent separation (601) and is further absorbed by the fluid (606);
  • FIG6c source of radiation is delivered by an optical waveguide (602) and it is further absorbed by the solid-state light-absorbing material (611) coated on the transparent separation (601);
  • FIG6d radiation (609) is focused by e.g., lens (610) and passes through a transparent separation (601) and it is absorbed by the solid-state light-absorbing material (611) coated on the transparent separation (601).
  • FIG6e source of radiation is delivered by an optical waveguide (602) and is further absorbed by the solid-state light-absorbing material (611) coated on the transparent separation (601).
  • Elastic coating of e.g., polyimide (612) contains the expanding metallic vapor within the blister;
  • FIG6f radiation (609) is focused by e.g., lens (610) and passes through a transparent separation (601) further it is absorbed by the solid-state light-absorbing material (611) coated on the transparent separation (601).
  • Elastic coating of e.g., polyimide (612) contains the expanding metallic vapor within the blister;
  • Figure 7 contains a schematic view of a needle assisted jet injection system using electromagnetic radiation as a driving force for the liquid jet actuation.
  • the system comprises two separate compartments; one for the light absorption driving fluid (705) and the second is the channel for the fluid content (702), the pressure is then transmitted by an elastic membrane (704); wherein in FIG7a a source of radiation is delivered to the chamber with the driving fluid (705) by an optical waveguide (706); and in FIG7b the radiation (710) is focused by an optical focusing element (711) into the chamber containing the driving fluid (705);
  • Figure 8 shows an example of the device described by the scheme of the Figure 1 ;
  • Figure 9 shows an example of the jet injection from the device depicted on the Figure 8; and Figure 10 is a schematic view of a system with a flexible tubing.
  • the present invention seeks to provide a solution to miniaturization of the jet injection technology by using optical energy as a driving force and delivery by means of optical fibers.
  • a fiber source of radiation e.g., a fiber optics
  • a fiber optics is used to deliver the light energy into a nozzle filled with a fluid, whereby the fluid is configured to absorb radiation in a spectrum of the used radiation.
  • the fiber source of radiation is in direct contact with the absorbing fluid. This enables to avoid any unwanted modulation by an other medium like a nozzle material or free space.
  • An intensity of the radiation is smaller than the laser-induced-damage-threshold (typically ⁇ 5 GW/cm 2 for silica step-index fiber, but can be higher for hollow-core fibers or photonic crystal fiber) of an optical fiber in the fiber optics, but higher than a threshold for the vapor bubble generation in the fluid, which depends on a nature of the fluid.
  • appropriate absorbing additives may be added to the fluid. Conditions for the bubble cavitation can be also secured by the appropriate choice of the laser source in the near infra red emitting spectrum which is the wavelength absorbed by water and other pharmaceutical solvents — this way additives can be avoided.
  • Interaction of the short pulse ( ⁇ 100 ns) laser radiation with the liquid can happen under heat and stress confined conditions which mitigates degrading effects on the sensitive formulations.
  • To facilitate coupling into the optical fiber it can be used tapered fiber with smaller and at the nozzle site.
  • the nozzle can be accompanied by the mechanism allowing disposable use where the end section of the fiber can be reconnected by fiber connector.
  • a focusing mechanism on the end of the fiber such as for example, but not exclusively, a ball lens or a graded-index lens.
  • Optical fibers with a smaller diameter, for example 50 pm, are more efficient in translation of the optical energy to the jet energy than thicker fibers, for example 200 pm.
  • a nozzle ending is in a gaseous environment and it is made from a hydrophilic material or a hydrophobic material equipped by a layer of the hydrophilic material at the opening, allowing the formation of a concave meniscus.
  • the laser radiation is absorbed which leads to a rapid vaporization of the fluid and consequent generation of the bubble.
  • the jet velocity is sufficient to penetrate into the substrate such as for example, but not exclusively, biological tissue.
  • the jet velocity is sufficient to pierce through the substrate such as for example, but not exclusively, biological tissue.
  • the jet is deposited on the top of the substrate such as for example, but not exclusively, biological tissue.
  • the aforementioned embodiment may be multiplied in single device to concurrently generate multiple injections.
  • the embodiment is modified for the operation in the liquid environment.
  • a curved liquid/air interface is secured. That may be realized, for example, by additional gas inlet channel leading to the nozzle opening allowing a controlled gas bubble creation between the substrate and the optical fiber end.
  • the absorption of laser radiation leads to the generation of the vapor bubble and thanks to the concave shape of the liquid/air interface formed by the gas bubble the jet emerges and is also further accelerated by the flow focusing effect.
  • the jet velocity is sufficient to penetrate into the substrate such as for example, but not exclusively, biological tissue.
  • the jet velocity is sufficient to pierce through the substrate such as for example, but not exclusively, biological tissue.
  • the jet is deposited on the top of the substrate and does not penetrate in.
  • the aforementioned embodiment may be multiplied in single device to concurrently generate multiple injections.
  • This can be achieved by splitting the radiation by optical element for example but not exclusively by a beam splitter, lens microarray, hologram, fiber-based splitter, or using a fiber bundle system.
  • Each partition of radiation can serve as the source for the cavitation event.
  • Parallel embodiment of nozzles can be arranged in a pattern. This may allow patterned deposition to target specific location of the tissue. Examples of the use of patterned arrangement may be in a localized distribution of dental anesthesia where specific arrangement can facilitate single tooth anesthesia or a needle- free based tattoo machine where this can allow new artistic expression extending a current single dot deposition to for example, but not exclusively multiple nozzles arranged in a line.
  • the substrate which may be a biological tissue
  • the substrate is partially or fully pierced by a short ( ⁇ 5 mm) and thin needle. This way a part of the mechanical barrier is overcome.
  • the needle is equipped with a pressure generating mechanism.
  • a pressure may be generated, for example, by the rapid phase transition initiated by laser radiation or an electrical discharge.
  • An actuation mechanism may be in the direct contact with the fluid or it may propagate through the separation unit transparent to the radiation.
  • radiation is delivered by the optical fiber.
  • radiation is focused by the free space optical element. Radiation may be absorbed directly by the fluid or by the solid-state light-absorbing material coated on the transparent separation unit being in contact with the fluid.
  • the solid-state light-absorbing material coating may be further equipped by the elastic coating of for example, but not exclusively, polyimide.
  • An additional layer may contain the expanding metallic vapor within but cause the layer deformation and creation of the expansion blister.
  • Each of the aforementioned embodiments may be multiplied in a single device to concurrently generate multiple injections.
  • Parallel embodiment of nozzles can be arranged in a pattern.
  • this scheme is used to enhance delivery from a microneedle array.
  • a system comprises two separate compartments: one for the highly absorptive driving fluid and the second is the channel for the functional fluid content for example drug, the pressure is then transmitted by an elastic membrane, or other movable unit.
  • a source of radiation is delivered by an optical waveguide.
  • the radiation is focused by an optical focusing element into the chamber containing the driving fluid.
  • the nozzle channel is tapered to achieve higher velocities.
  • tubing leading to a nozzle is made from flexible material, for example but not exclusively Teflon.
  • flexible material for example but not exclusively Teflon.
  • Figure la is a schematic depiction of a compact system consisting of a nozzle (101) made out of hydrophilic material or hydrophobic material equipped by a coating made with the hydrophilic material allowing a concave meniscus (103) to emerge between the fluid (104) and a gaseous environment (102).
  • Laser pulse radiation (105) is delivered by an optical waveguide (106), e.g., an optical fiber, and it is in direct contact with the fluid (104) which is capable of absorption in the spectrum of the laser pulse radiation (105).
  • Figure lb shows a drawing of a jet (107) emerging after the energy of the laser pulse radiation (105) is absorbed. Absorption leads to a rapid vaporization of the fluid (104) and generation of the bubble (109).
  • the jet (107) emerges from the center of the channel of the nozzle (101) and it is further accelerated by the flow focusing effect.
  • the jet velocity is sufficient to penetrate into a substrate (108).
  • the jet velocity is sufficient to pierce through the substrate (108).
  • the jet is deposited on the top of the substrate (108) and does not penetrate in.
  • FIG 2 is a schematic example of an arrangement consisting of multiple systems described in the Figure 1 (201) to concurrently generate multiple liquid microjets in the air environment.
  • Figure 3 is a schematic drawing of a compact system adjusted for the generation of the liquid microjet (308) in the liquid environment (301).
  • a gas channel (305) allowing bubble (306) creation at an outing of the gas channel (305) in the fluid (304) of the nozzle.
  • Laser radiation (303) is delivered by an optical waveguide (302), e.g., an optical fiber, and it is in the direct contact with the fluid (304) which is capable of absorption in the spectrum of the laser pulse radiation (303).
  • the Figure 3b shows a drawing of a jet (308) emerging after the energy of the laser pulse (303) is absorbed. Absorption leads to a rapid vaporization of the fluid (304) and generation of the bubble (307). As the bubble (307) expands it pushes the liquid out of the nozzle. Thanks to the concave shape of the liquid/air interface formed by the bubble (306) the jet (308) emerges from the bubble (306) inner interface and it is further accelerated by the flow focusing effect.
  • the jet velocity is sufficient to penetrate into the substrate (309).
  • the jet velocity is sufficient to pierce through the substrate (309).
  • the jet is deposited on the top of the substrate (309) and does not penetrate in the substrate.
  • FIG 4 is the schematic depiction of the needle assisted jet injection.
  • a substrate (403) for example a tissue, is pierced (404) by a needle (401).
  • the needle (401) is equipped with a pressure generating mechanism (402).
  • Pressure can be generated by the rapid phase transition of a fluid (407) initiated by for example, but not exclusively, laser radiation or an electrical discharge.
  • the created bubble (405) expands and pushes the fluid (407) out of the needle (401) in the substrate (403).
  • Fluid (407) may be deposited in a certain depth (406) depending on the energy of the actuation.
  • Figure 5 is a schematic example of an arrangement consisting of multiple systems described in the Figure 4 (501) to concurrently perform needle-assisted jet injection.
  • Parallel embodiment of nozzles can be arranged in a pattern.
  • FIG 6a is a schematic view of a needle assisted jet injection system.
  • the substrate (605) for example a tissue, is pierced by a needle (604).
  • the needle (604) is equipped with a pressure generating mechanism (602), for example a phase transition initiated by a laser radiation (603).
  • the source of radiation is comparted by a separation (601) transparent to the radiation (603) and it is not in direct contact with the fluid (606).
  • the created bubble (607) expands and pushes the fluid (606) out of the needle (604) in the substrate (605).
  • Fluid (606) may be deposited in a certain depth (608) depending on the energy of the actuation.
  • Figure 6b presents the scheme of a modification of the system from the Figure 6a.
  • the radiation (609) is focused by a focusing element (610) for example a lens, and passes through a transparent separation (601). It is further absorbed by the fluid (606) which is capable of absorption of the radiation (609).
  • Figure 6c presents the scheme of a modification of the system from the Figure 6a.
  • the radiation is delivered by an optical waveguide (602) and it is further absorbed by the solid-state light-absorbing material (611) coated on the transparent separation (601). Absorption leads to phase change in the adjacent fluid (606) and generation of the vapor bubble (607).
  • Figure 6d presents the scheme of a modification of the system from the Figure 6a.
  • the radiation (609) is focused by the focusing element (610), for example the lens, and passes through a transparent separation (601). It is further absorbed by the solid- state light-absorbing material (611) coated on the transparent separation (601). Absorption leads to phase change in the adjacent fluid (606) and generation of the vapor bubble (607).
  • Figure 6e presents the scheme of a modification of the system from the Figure 6a.
  • the source of radiation is delivered by an optical waveguide (602) and is further absorbed by the solid-state light-absorbing material (611) coated on the transparent separation (601).
  • Elastic coating of e.g., polyimide (612) contains the expanding metallic vapor within the blister (617). Deformation of the blister pushes the liquid out of the needle (604) in the substrate (605).
  • Figure 6f presents the scheme of a modification of the system from the Figure 6a.
  • the radiation (609) is focused by the focusing element (610) for example the lens, and passes through a transparent separation (601); further it is absorbed by the solid- state light-absorbing material (611) coated on the transparent separation (601).
  • Elastic coating of e.g., polyimide (612) contains the expanding metallic vapor within the blister (617). Deformation of the blister pushes the liquid out of the needle (604) in the substrate (605).
  • Figure 7a is a schematic view of a needle assisted jet injection system using electromagnetic radiation as a driving force for the liquid jet actuation.
  • the substrate (708) for example a tissue, is pierced by a needle (701).
  • the needle (701) is equipped with a pressure generating mechanism (706), for example phase transition initiated by a laser radiation.
  • System consists of two separate compartments; one (703) for the light absorption driving fluid (705) and the second is the channel (702) for the fluid content.
  • Phase changing mechanism (706) for example laser radiation generates a bubble (707). Expansion of the bubble (707) leads to a fast deformation of the elastic membrane (704) which pushes the liquid contain out of the needle (701) deeper (709) into the substrate (708).
  • Figure 7b presents the scheme of a modification of the system from the Figure 7a.
  • the radiation (710) is focused by an optical focusing element (711) into the chamber containing the driving fluid (705).
  • Absorption leads to the phase transition and subsequent bubble generation (707).
  • Expansion of the bubble (707) leads to a fast deformation of the elastic membrane (704) which pushes the liquid contain out of the needle (701) into the substrate (708).
  • Figure 8 shows an example of the device using optical pulse as the actuation mechanism for generation of the liquid jet in the air environment.
  • a laser pulse generator (5 ns, 532 nm, Nd:YAG) is coupled into the optical fiber (802).
  • a fluid and the optical fiber (802) channel are connected by a T-junction (803) which is further plugged into a round glass capillary (804).
  • the length of the capillary in this particular example is 95 mm and the outer diameter is 1.2 mm.
  • Figure 9 shows an image sequence from an ultrafast camera of the generated liquid jet from the device depicted in the Figure 8 and its penetration into a gel mimicking mechanical properties of human body soft tissues.
  • a diameter of the optical fiber is 50 pm
  • capillary inner diameter is 300 pm
  • the pulse energy is 220 pj
  • jet velocity is 140 m/s.
  • FIG 10 is a schematic view of a system with a flexible tubing.
  • the liquid jet (1001) is generated from a nozzle opening (1002) by means of optically induced cavitation (1003). Liquid and the fiber are embarked in a flexible tubing (1004).

Abstract

L'invention concerne des systèmes et des procédés pour la génération de jets microfluidiques fournissant un outil pour une administration très précise et localisée, par exemple, de médicaments. La solution proposée permet de surmonter les inconvénients liés à la miniaturisation d'une technologie d'injection à jet grâce à l'utilisation d'énergie laser en tant que mécanisme d'entraînement et de fibres optiques pour sa distribution. La résolution des problèmes associés à la miniaturisation peut permettre de construire de nouveaux outils compatibles avec des techniques chirurgicales minimalement invasives, la parallélisation élevée d'unités d'injection à jet ou la conception de nouveaux dispositifs d'injection ergonomiques.
PCT/IB2021/050625 2020-01-28 2021-01-27 Système et procédé pour la génération d'un jet microfluidique à partir d'un dispositif compact WO2021152476A1 (fr)

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US6913605B2 (en) 1999-05-21 2005-07-05 The Board Of Trustees Of The Leland Stanford Junior University Microfluidic devices and methods for producing pulsed microfluidic jets in a liquid environment
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